HDAC6, a new therapeutic target for chronic pain Chronic neuropathic pain is a severe medical condition and an important unmet medical need. Current first-line medications successfully provide relief in a subset of patients but their activity usually require weeks to months of administration a delay also observed in preclinical models. In contrast, recent preclinical studies show that broad-acting histone deceatylase (HDAC) inhibitors, such as trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA), rapidly relieve hyperalgesia in various models of neuropathic pain. This points to HDAC inhibition as a promising avenue for the development of new treatments. However, the exact mechanisms underlying this rapid analgesic activity remain elusive. Characterizing the specific HDAC isoforms, the HDAC substrates, and brain networks that mediate these analgesic effects, will provide important insights for the design of newer medications with improved side-effect profile. Our preliminary data indicate that the selective pharmacological blockade of HDAC6, a mainly cytoplasmic class IIB isoform, is sufficient to fully recapitulate the analgesic activity of broad acting HDAC inhibitors, even though this isoform does not deacetylate chromatin in vivo. Under Aim I we will combine state of the art isoform-selective pharmacological probes and conditional loss of function of HDAC6 using a floxed HDAC6 allele to investigate the role of HDAC6 in pain- like behaviors associated with peripheral nerve injury. Specifically, we will use the spare nerve model of neuropathic pain to test the hypothesis that HDAC6 activity at certain supraspinal sites, such as the serotonergic Raphe Nuclei (RN), is necessary and sufficient for the development of sensory hypersensitivity and/or depression-like behaviors. Under Aim II, we will track changes in the expression and activity of HDAC6 at successive time-points after the induction of nerve injury. We will also monitor changes in the phosphorylation of HDAC6 and the acetylation of Hsp90 and alpha-tubulin, two validated targets of HDAC6, under neuropathic pain states. Finally, we will assess the impact of HDAC6 in cytokine expression in the RN.